Research ArticleCancer

A first-in-human phase 0 clinical study of RNA interference–based spherical nucleic acids in patients with recurrent glioblastoma

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Science Translational Medicine  10 Mar 2021:
Vol. 13, Issue 584, eabb3945
DOI: 10.1126/scitranslmed.abb3945

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A golden opportunity to treat glioblastoma

Glioblastoma (GBM) is a difficult cancer to treat, partly due to the blood-brain and blood-tumor barriers. Kumthekar et al. studied NU-0129, spherical nucleic acids consisting of gold nanoparticle cores conjugated with small interfering RNA oligonucleotides targeting Bcl2L12, for the treatment of GBM. After performing toxicology studies in cynomolgus monkeys, the authors conducted a first-in-human single-arm clinical trial of very low-dose NU-0129 in eight patients with recurrent GBM. By analyzing gold accumulation, the authors found that NU-0129 passed through the blood-brain barrier and accumulated in the tumor, where it reduced Bcl2L12 protein abundance. These results suggest that spherical nucleic acid nanoconjugates can potentially treat GBM.


Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference–based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment–related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129–treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.

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